Orexins are a newly identified peptide family comprised of two peptides, orexin-A and orexin-B, which are synthesized by a limited population of neurons located within the lateral and dorsal hypothalamus. Initially, these peptides were demonstrated to stimulate feeding, when administered in relatively high doses. However, orexin neurons project widely throughout the brain and spinal cord, including to regions associated with the regulation of behavioral state. Consistent with these observations, substantial evidence suggests dysregulation of orexin neurotransmission is associated with the sleep/arousal disorder, narcolepsy. Further, recent evidence suggests that these peptides exert an activating influence on forebrain and behavioral state. In preliminary studies, the PI has observed potent arousal-enhancing actions of orexin when administered into sleeping/resting animals, at doses substantially below those that elicit feeding. The neural mechanisms that underlie these arousal-enhancing actions remain unknown. Work by the PI demonstrates that the locus coeruleus (LC)-noradrenergic system exerts a potent activational influence on forebrain neuronal and behavioral activity states. These actions derive, in part, from actions of norepinephrine within a subset of basal forebrain structures. Given this, it is of interest that orexin-containing fibers innervate LC, these same basal forebrain structures, as well as other regions implicated in the regulation of behavioral state. The proposed studies will complete preliminary studies that characterize the dose-dependent effects of orexin-A and -B on behavioral state. Additionally, these studies will characterize the anatomical organization of the orexin efferent projection system. Finally, these studies will provide initial assessment of a number of potential neural mechanisms underlying orexin-enhanced arousal. Specifically, the extent to which orexins alter behavioral state via actions within certain basal forebrain and brainstem structures will be examined. These studies will provide a better understanding of the neurobiology of orexin, the neurobiology of sleep and waking, and the potential role of orexin in narcolepsy and other disorders of arousal.